Multi-unit delivery system

ABSTRACT

A dispenser for use in a fluid environment which is capable of delivery of a plurality of discrete drug-containing units in any desired delivery pattern or profile.

RELATED PATENT APPLICATIONS

This application is a continuation-in-part of U.S. Pat. Application Ser.No. 07/283,772, filed on Dec. 13, 1988, which in turn is acontinuation-in-part of U.S. patent application Ser. No. 07/270,730,filed on Nov. 14, 1988, now abandoned, which in turn is acontinuation-in-part of U.S. patent application Ser. No. 07/066,905,filed on June 25, 1987, now abandoned, which applications are assignedto ALZA Corporation and are incorporated herein by reference, andbenefit is claimed of their filing dates.

This application is related to the copending, coassigned U.S. patentapplications Ser. No. 07/066,906, filed on June 25, 1987 of Wong et alfor a Multi-Layer Delivery System, now U.S. Pat. No. 4,874,388; Ser. No.07/270,160, filed on Nov. 14, 1988 of Wong et al for Multi-LayerDelivery System; and Ser. No. 07/283,631, filed on Dec. 13, 1988 of Wonget al for Multi-Layer Delivery System.

FIELD OF THE INVENTION

This invention relates to patterned drug delivery. More particularly,this invention relates to patterned drug delivery by means of aplurality of individual drug delivery units or tablets. Still moreparticularly, but without limitation thereto, this invention relates todelivery of multi-agents orally or in other media in a preprogrammeddelivery profile.

DEFINITION OF TERMS

The expressions "active agent" and "drug" are used interchangeably andas used herein broadly include any compound, PG,3 composition of matteror mixture thereof that can be delivered from the system to produce abeneficial and useful result. This includes pesticides, herbicides,germicides, biocides, algicides, rodenticides, fungicides, insecticides,anti-oxidants, plant growth promoters, plant growth inhibitors,preservatives, anti-preservatives, disinfectants, sterilization agents,catalysts, chemical reactants, fermentation agents, foods, foodsupplements, nutrients, cosmetics, drugs, vitamins, sex sterilants,fertility inhibitors, fertility promoters, air purifiers, microorganismattenuators and other agents that benefit the environment of use.

The terms "active agent" and "drug" as used herein further include anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect or effects in animals, including warmblooded mammals, humans and primates, avians, domestic household, sportor farm animals such as dogs, sheep, goats, cattle, horses and pigs, oris administered to laboratory animals such as mice, rats and guineapigs, to fish, reptiles, zoo and wild animals. The active drug which canbe delivered includes inorganic and organic compounds, including,without limitation, those materials that act upon the central nervoussystem such as hypnotics and sedatives, psychic energizers,tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents,analgesics, anti-inflammatories, local anesthetics, muscle contractants,antimicrobials, antimalarials, hormonal agents including contraceptives,sympathomimetrics, diuretics, lipid regulating agents, antiandrogenicagents, antiparasitics, neoplastics, antineoplastics, hypoglycemics,nutritionals, fats, ophthalmics, electrolytes and diagnostic agents.

The terms "drug unit," "dosage unit," "active agent unit" and "activeagent dosage unit" as used herein include units that are capable ofmaintaining their physical configuration and chemical integrity whilehoused within the dispenser. This includes, without limitation, tabletswith or without a density element; matrix tablets; pellets and elongatedtablets where the height-to-diameter ratio exceeds one; capsules;elementary osmotic pumps, such as that described in U.S. Pat. No.3,845,770; mini osmotic pumps, such as those described in U.S. Pat. Nos.3,995,631, 4,034,756 and 4,111,202; and multichamber osmotic systemsreferred to as push-pull and push-melt osmotic pumps, such as thosedescribed in U.S. Pat. Nos. 4,320,759 and 4,449,983; all of which areincorporated herein by reference.

As used herein the expression "external fluid" includes water and otherbiological fluids.

BACKGROUND OF THE INVENTION

The concept of patterned drug delivery covers a broad range of systemsfrom time release capsules whose components have coatings which erode atdifferent rates, to controlled release rate tablets which operate byosmosis.

Despite the development of the art, however, there remains a continuingneed for improved methods and systems for providing controlled drugrelease profiles.

SUMMARY OF THE INVENTION

An object of this invention is to provide sequential timing anddispensing of dosage units containing the same or different activeagents.

Another object of this invention is to provide sequential timing anddispensing of two dosage units simultaneously, the units containing thesame or different active agents.

Yet another object of this invention is to provide both a novel and auseful agent formulation delivery system that is self-contained,self-powered, and also represents an improvement in the delivery art.

These and other objects are demonstrated by the present inventionwherein an active agent dispenser for use in a fluid-containingenvironment comprises a rigid housing, a plurality of movable activeagent units filling a portion of the housing, a fluid-activated drivingmember for dispensing the active agent units filling the remainder ofthe housing and an active agent unit outlet means.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in further detail with reference to theaccompanying drawings wherein:

FIG. 1 is a partial cross-sectional view of the dispenser of thisinvention, illustrating one embodiment of the dispensing configuration;

FIG. 2 is a partial cross-sectional view of the dispenser of thisinvention, illustrating a second embodiment of the dispensingconfiguration;

FIG. 3 is a partial cross-sectional view of the dispenser of thisinvention, illustrating still another embodiment of the dispensingconfiguration;

FIG. 4 is a partial cross-sectional view of one embodiment of thedriving member for the dispenser of this invention, utilizing ahydrophilic expandable member;

FIG. 5 is a partial cross-sectional view of a second embodiment of thedriving member for the dispenser of this invention, utilizing anosmotically effective solute;

FIG. 6 is a partial cross-sectional view of another embodiment of thedriving member for the dispenser of this invention, utilizing anelementary osmotic pump;

FIG. 7 is a partial cross-sectional view of another embodiment of thedriving member for the dispenser of this invention, utilizing agas-generating composition;

FIG. 8 is a partial cross-sectional view of the dispenser of thisinvention, illustrating another embodiment of the dispensingconfiguration;

FIG. 9 is a partial cross-sectional view of an embodiment of the housingfor the dispenser of this invention, having a first walled section and asecond walled section;

FIG. 10 is a partial cross-sectional view of another embodiment of thehousing for the dispenser for this invention with means for releasablyholding an insert member comprising an expandable member for pushingtablets out of the dispenser;

FIG. 11 is a partial cross-sectional view of still another embodiment ofthe housing having a first walled section and an engaging second walledsection;

FIG. 12 is a partial cross-sectional view of another embodiment of thehousing for the dispenser of this invention having a tablet containingsection and a driving force section joined as releasable engagingstructural member sections;

FIG. 13 is a partial cross-sectional view of still another embodiment ofthe housing where the end is tapered;

FIG. 14 is a partial cross-sectional view of the dispenser of thisinvention, illustrating another embodiment of the dispensingconfiguration;

FIG. 15 is a cross-sectional view of the dispenser of this invention,illustrating another embodiment of the dispensing configuration and thehousing; and

FIG. 16 shows the release rate for a two-pulse drug delivery system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention can provide a variety of drug delivery profilesincluding, but not limited to, pulsed delivery of a single drug or drugformulation, pulsed delivery of a sequence of different drugs or drugformulations, pulsed delivery of one drug or drug formulationsuperimposed on continuous delivery of a different drug or drugformulation, pulsed delivery of two drugs or drug formulationssimultaneously, and simultaneous continuous delivery of several drugs ordrug formulations.

This invention is particularly suited to the delivery ofpharmacologically active peptides and protein anabolic hormones such asgrowth promoting hormones related to the endocrine system comprising,for example, porcine growth promoting hormone, bovine growth promotinghormone, equine growth promoting hormone, ovine growth promotinghormone, human growth promoting hormone, growth promoting hormonesderived by extraction and concentration from pituitary and hypothalamusglands, growth promoting hormones produced by recombinant DNA methods,bovine growth promoting hormone as described in Nucleic Acid Res., Vol.10, p 7197 (1982), ovine growth promoting hormone as described in Arch.Biochem. Biophys., Vol. 156, p 493 (1973), and porcine growth promotinghormone as described in DNA, Vol. 2, pp 37, 45 (1983). Also included arepolypeptides such as growth hormone, somatropin, somatotropin,somatomedin-C, gonadotropic releasing hormone, follicle stimulatinghormone, luteinizing hormone, LH-RH, growth hormone releasing factor,gonadotropin releasing factor, insulin, colchicine, chorionicgonadotropin, oxytocin, vasopressin, adrenocorticotrophic hormone,epidermal growth factor, prolactin, somatostatin, cosyntropin,lypressin, polypeptides such as thyrotropin releasing hormone, thyroidstimulating hormone, secretin, pancreozymin, enkephalin, glucagon, andthe like. The active agents and their dosage unit amounts are known tothe art in The Pharmacological Basis of Therapeutics, by Gilman,Goodman, Rall and Murad, 7th Ed., (1985) published by MacMillanPublishing Co., N.Y.; in Pharmaceutical Sciences, Remington, 17th Ed.,(1985) published by Mack Publishing Co., Easton, Pa.; and in U.S. Pat.No. 4,526,938.

The drug delivery system or dispenser of this invention is designed todeliver a plurality of discrete longitudinally aligned individual drugunits by the linear expansion of a fluid-activated driving member. Thedrug units are such that they retain their physical and chemicalintegrity while contained within the system and do not substantiallycommence delivery of active agent until after they have been dispensedinto the environment. The dispenser is comprised of a dispensingcomponent and a driving component, representative embodiments of whichare disclosed herein. FIGS. 1, 2, 3 and 8 illustrate various embodimentsof the dispensing component suitable for use in the dispenser of thisinvention. These configurations can be combined with various embodimentsof the driving component, representative embodiments of which areillustrated in FIGS. 4-7, and of the housing structure itself, shown inFIGS. 1, 4, 6, 9-13 and 15. The drug delivery system or dispenser ofthis invention may, alternately, be comprised of a driving component andtwo dispensing components, a representative embodiment of which isillustrated in FIG. 14.

The dispensing and driving component designs are for use in afluid-containing environment and are merely exemplary of the numerousembodiments suitable for use in this invention. The portion of thehousing adjacent to the dispenser component is of a material which maybe either semipermeable or substantially impermeable to the passage ofexternal fluid. Typical suitable impermeable materials include, withoutlimitation, polyethylene, compressed polyethylene fine powder,polyethylene terephthalate (Mylar®), plasticized polyvinyl chloride,metal-foil polyethylene laminates, neoprene rubber, natural gum rubberand Pliofilm® (rubber hydrochloride). These materials are additionallyflexible, insoluble and chemically compatible with the active agentcontained in the units positioned therein, and, in the instance ofproviding a drug or like depot within the body of a living organism, arebiologically inert, non-irritating to body tissues and non-allergenic.Additional suitable materials include polystyrene, polypropylene,polyvinyl chloride, reinforced epoxy resin, polymethylmethacrylate,etc., sheet metal (e.g., aluminum, copper, steel, etc.), galvanizedpipe, or styrene/acrylonitrile copolymer. Again, for drug depotapplications the same are advantageously biologically inert,non-irritating to body tissue and non-allergenic. Suitable semipermeablematerials include, without limitation, all cellulosic polymers such ascellulose acetates, ethyl cellulose, methyl cellulose, cellulose acetatebutyrate, cellulose acetate propionate, etc., or impermeable materialblended with a hydrophilic polymer or a low molecular weightwater-soluble enhancer to render the material semipermeable.

Many other materials including those which are biologically acceptableare suitable for fabrication of the impermeable component of the deviceof this invention. While the impermeable portion of the housing haspreviously been described as being insoluble under the conditions and inthe environment of intended use, it is also within the scope of theinvention that such materials be insoluble only during the period ofsaid intended use, thereafter dissolving or otherwise degrading into theenvironment of the device. Thus, a dispenser is here contemplated whichis unaffected by its environment, solubility-wise, at the situs of use,or which is only slightly soluble during the period of intended use,such that once all the units have been dispensed, it will then dissolveor erode away, leaving no objectionable residue or empty container atthe said situs of use.

The portion of the housing adjacent to the driving component must besemipermeable so as to allow for passage of external fluid, since thedriving member is fluid-activated. Suitable materials will be discussedat length with regards to specific embodiments of the driving member.

The dispensing component shown in FIG. 1 is comprised of a rigid housingmember 20. Housing 20 is also designed with an outlet means, exit port22. A plurality of movable discrete units 24, 26, 28, 30 and 32 arealigned within the housing 20. This configuration is merelyillustrative, and the dispenser may have numerous drug units other thanthe number shown in FIG. 1.

The drug units are in the form of a solid core or a matrix tablet or inany of a variety of forms which are capable of maintaining theirphysical and chemical integrity, i.e. do not erode. The driving member34 operates to displace the units towards the exit port 22. As unit 24comes into contact with the exit, it is dispensed into the environmentand begins to deliver drug in a controlled or semi-controlled fashion.Once unit 24 is dispensed, linear displacement pushes unit 30 throughthe housing 20 so that it then comes into contact with exit 22 and islikewise dispensed. This continues until the dispenser is depleted ofdrug units.

The units can provide a variety of drug delivery profiles depending upontheir composition. They can all contain the same drug(s) at the sameconcentration(s) to deliver identical pulses of drug over time as eachunit is dispensed, or they can contain the same drug(s) at differentconcentrations to give different pulses of drug. Alternately, the unitsmay contain different drugs or drug formulations.

The drug units of this invention may also contain binders, lubricants,and, optionally, excipients such as compounds to stabilize the drug orto facilitate erosion. An example of a suitable composition ascontemplated by this invention is about 80-95 wt% drug, about 2-3 wt%binder, about 0.1-5 wt% lubricant, about 1-15 wt% excipient tofacilitate disintegration or erosion and about 1-6 wt% excipient tostabilize the drug.

Materials suited for use in formulating the drug units of this inventionare well known in the art and are fully described in texts such asPharmaceutical Sciences, Remington, Chapter 87 (supra). Binders whichimpart cohesive qualities include, without limitation, starch, gelatin,agar, natural and synthetic gums, carboxycellulose,carboxymethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, cellulose acetate, polyurethane andwaxes. Lubricants serve numerous purposes including improving the rateof flow of the granulated particles and facilitating the actualmanufacture of the units. Suitable lubricants include, withoutlimitation, talc, starch, zinc stearate, aluminum stearate, magnesiumstearate, calcium stearate, boric acid, sodium chloride, paraffin,stearic acid, low melting point waxes, hydrogenated vegetable oils andsaturated fatty acid esters. The units may also include a disintegrantsuch as lightly cross-linked polyvinyl pyrrolidone, corn starch, potatostarch, Veegum®, bentonite and citrus pulp. It may also be desirable toinclude stabilizers for the drug. These include, without limitation,sodium bisulfite and histidine HCl.

The drug unit composition may also be modified to include about 0.1-5wt% of a surfactant and/or about 0.01-2 wt% of an anti-oxidant, forexample. Suitable surfactants include, without limitation, sorbitanmonostearate, polysorbate 80 USP [polyoxyethylene (20) sorbitanmonooleate], and polyoxyethylene 4 stearate. Suitable anti-oxidantsinclude, without limitation, tertiary butyl-4-methoxyphenol (mixture of2- and 3-isomers), 2,6-ditertiary butyl-p-cresol, propyl gallate,6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin) andnordihydroguaiaretic acid (NDGA).

In a preferred embodiment, units 24, 26 and 28 contain a drug or drugformulation and alternate units 30 and 32 contain no drug, such thatwhen they are dispensed, an "off" period is provided, during which timeno drug is being delivered. The additional advantage of this"alternating" configuration is that once unit 24 is dispensed, thesurface of unit 30 is exposed and may begin the erode. Having 30 as anon-drug-containing unit guarantees that the drug being delivered to theenvironment comes from the dispensed unit rather than from the unitsstill retained within the housing.

The dispensing configuration shown in FIG. 2 is also designed to delivera plurality of discrete units to the environment, and operates similarlyto the embodiment of FIG. 1. In FIG. 1, the geometry of the unitspermits close alignment so as not to have any space between adjacentunits. This aspect is not critical to the effectiveness of theinvention, as is shown by FIG. 2 where the units are curved andtherefore do not fit closely together within the housing.

The dispensing configuration of FIG. 2 is comprised of a rigid housing38 and a plurality of discrete drug units 40, 42 and 44, alignedtherein. Three drug units are shown, but in actual application anynumber of units may be used. The driving member 46 displaces the unitsat the desired rate and dispenses them individually through the exitport 48.

The drug units, 40 for example, can be elementary osmotic pumps ormini-osmotic pumps, for example. They can also be coated with adegradable coating to delay delivery until the units are actuallydispensed into the environment.

The dispensing configuration shown in FIG. 3 is comprised of a housingmember 50 and a plurality of discrete drug units 52, 54, 56 and 58aligned therein. As with FIGS. 1 and 2, the number of units shown ismerely illustrative and is not intended to limit the invention in anymanner.

The driving member 60 operates to linearly displace the units anddispense them through the exit port 62. The units, 52 for example, arecomprised of a plastic or polyethylene cap 64 with a drug mixture 66compressed within. The units may be bowl-shaped as shown or they may bebox-shaped to hold a larger quantity of drug. The units are separated bypartitions 68, 70, 72 and 74, which can be a rigid solid or a gel. Asthe unit 52 is dispensed, the drug mixture 66 is exposed to theenvironment (external fluid) and is thus delivered. Subsequently, thepartition 68 is dispensed through the exit port 62.

This dispensing configuration provides pulsed drug delivery. As unit 52is dispensed, a burst of drug is delivered which is followed by anotherpulse when unit 54 is dispensed and so forth. The units may contain thesame drug in the same or different concentrations, or different drugs.In this manner, any pattern of delivery may be fashioned.

EXAMPLE 1

The dispenser of FIG. 3 is especially suited for treatment of helminthinfections in ruminants, specifically cattle. Depending upon the natureof delivery desired, several drug formulations can be used in thisdispenser.

A suitable drug formulation is comprised of about 80 weight percentHapadex®, which is an anthelmintic agent for cattle sold bySchering-Plough Corporation. About 0.5 grams of the formulation 66 iscompressed into cap 64 to form unit 52. Units 54, 56 and 58 are alsofilled with the drug formulation. However, if an off period is desired,units 52 and 56 can contain drug and the alternate units 54 and 58 canbe empty.

For fast pulse delivery of Hapadex®, the drug formulation is 100% drug.However, this system can be designed to provide a short-duration pulsewhere the drug formulation has a gas generator contained therein.Especially suitable is a formulation comprised of about 80% Hapadex® andabout 20% citric acid/sodium bicarbonate.

If a longer period of delivery is desired, a disintegrating agent suchas Ac-Di-Sol® (FMC Corporation), otherwise known as croscarmellosesodium, can be incorporated into the drug formulation in an amount up to20 weight percent.

For even longer duration of drug delivery, the drug formulation can be80% Hapadex® and 20% polymer, such as Polyox® (polyethylene oxidepolymers) or hydroxypropylmethylcellulose.

For rumenal systems, an important criteria is that the system remain inthe rumen of an animal over a prolonged period of time. This isaccomplished by placement of a density element within the dispenser. Thehousing 50 itself may be the density element. Alternately, one of thepartitions, 74 for example, can act as the density element. In stillanother embodiment, unit 58 can be a density element, placed so as toremain within the housing 50 after all of the drug-containing units havebeen dispensed.

The density element suitable for use in the dispenser of this inventionmust be dense enough to retain the dispenser in the rumen-reticular sacof a ruminant. The presence of a density element allows the dispenser toremain in the rumen over a prolonged period of time rather than lettingit pass into the alimentary tract and be eliminated therefrom. As thedispenser remains in the rumen, a beneficial agent can be delivered tothe ruminant at a controlled rate over an extended period of time.Generally, a density element will have a density of from about 0.8 to 8,or higher, with the density in a presently preferred embodimentexhibiting a specific gravity of from about 2.2 to 7.6. For theruminants cattle and sheep, it is presently preferred that the densityelement exhibit a density such that there is a resulting dispenserdensity of about 3. Materials that have a density that can be used forforming a suitable density element include iron, iron shot, iron shotcoated with iron oxide, iron shot magnesium alloy, steel, stainlesssteel, copper oxide, a mixture of cobalt oxide and iron powder, and thelike.

Exemplary of drugs that are soluble or very soluble in water and can bedelivered by the dispenser systems of this invention includeprochlorperazine edisylate, ferrous sulfate, aminocaproic acid,potassium chloride, mecamylamine hydrochloride, procainamidehydrochloride, amphetamine sulfate, benzphetamine hydrochloride,isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazinehydrochloride, bethanechol chloride, metacholine chloride, pilocarpinehydrochloride, atropine sulfate, methscopolamine bromide, isopropamideiodide, tridihexethyl chloride, phenformin hydrochloride,methylphenidate hydrochloride, histidine hydrochloride, copper sulfate,and mixtures thereof.

Exemplary of agents that have limited solubility or are very slightlysoluble or insoluble in water and biological fluids and can be deliveredby the dispenser systems of this invention include diphenidol, meclizinehydrochloride, prochlorperazine maleate, gemfibrozil, thiethylperazinemaleate, anisindione, diphenadione, erythrityl tetranitrate, digoxin,isoflurophate, reserpine, azetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, flutamide, nilutamide(anandron), chlormadinone acetate, phenaglycodol, allopurinol, aluminumaspirin, methotrexate, acetyl sulfisoxazol, erythromycin, and mixturesthereof, steroids including corticosteroids such as hydrocortisone,hydrocorticosterone acetate, cortisone acetate and triamcinolone,anhydrogens such as methyltesterone, esterogenic steroids such as17-β-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether andestradiol, progestational steroids such as prednisolone, 17-α-hydroxy-progesterone acetate, 19-nor-progesterone, norethindrone,progesterone and norethynodrel, and the like.

The drug can also be in the various chemical and physical forms such asuncharged molecules, molecular complexes, and pharmacologicallyacceptable acid addition and base addition salts such as hydrochlorides,hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrate,borate, acetate, maleate, tartrate, oleate and salicylate. For acidicdrugs, salts of metals, amines or organic cations, for examplequaternary ammonium, can be used. Derivatives of drugs such as esters,ethers and amides can be used alone or mixed with other drugs. Also, adrug which is water insoluble can be used in a form that, on its releasefrom the dispenser, is converted by enzymes, hydrolyzed by body pH orother metabolic processes to the original form, or to a biologicallyactive form.

The dispensing configuration of FIGS. 1, 2 and 3 can be combined withany of the driving members illustrated in FIGS. 4, 5, 6, and 7 toprovide a tailored drug delivery system.

FIG. 4 illustrates a driving member system 76 utilizing an expandabledriving member 78 comprised of an external fluid-insoluble, externalfluid-swellable composition. Member 78 is encased in housing 80 which isa semipermeable membrane substantially permeable to the passage of anexternal fluid and substantially impermeable to the passage of anyingredients contained in member 78. The driving member 78 is positionedadjacent to one of the drug units at interface 82.

External fluid is imbibed through the housing 80 by the expandablehydrophilic member 78 in a tendency toward osmotic equilibrium tocontinuously swell and expand member 78. Member 78 expands whilemaintaining an intact immiscible boundary at interface 82, defined bythe surface of drug unit 86 and expandable member 78.

Expandable member 78 has a shape that corresponds to internal shape ofhousing 80 and is preferably made from a hydrogel composition. Thehydrogel composition is noncross-linked or optionally cross-linked andit possesses osmotic properties, such as the ability to imbibe anexternal fluid through semipermeable housing 80, and to exhibit anosmotic pressure gradient across semipermeable housing 80 against afluid outside the dispenser system. The materials used for forming theswellable, expandable member 78 are polymeric materials neat andpolymeric materials blended with osmotic agents that interact with wateror a biological fluid, absorb the fluid and swell or expand to anequilibrium state. The polymer exhibits the ability to retain asignificant fraction of imbibed fluid in the polymer molecularstructure. The polymers in a preferred embodiment are gel polymers thatcan swell or expand to a very high degree, usually exhibiting a 2- to50-fold volume increase. The swellable, hydrophilic polymers, also knownas osmopolymers, can be noncross-linked or lightly cross-linked. Thecross-links can be covalent, ionic or hydrogen bonds with the polymerpossessing the ability to swell in the presence of fluid, and whencross-linked it will not dissolve in the fluid. The polymer can be ofplant, animal, or synthetic origin. Polymeric materials useful for thepresent purpose include poly(hydroxyalkyl methacrylate) having amolecular weight of from 5,000 to 5,000,000; poly(vinyl pyrrolidone)having a molecular weight of from 10,000 to 360,000; anionic andcationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohol)having a low acetate residual; a swellable mixture of agar andcarboxymethyl cellulose; a swellable composition comprising methylcellulose mixed with a sparingly cross-linked agar; a water-swellablecopolymer produced by a dispersion of finely divided copolymer of maleicanhydride with styrene, ethylene, propylene, or isobutylene; awater-swellable polymer of N-vinyl lactams; swellable sodium salts ofcarboxylmethyl cellulose; and the like.

Other gelable, fluid-imbibing and retaining polymers useful for formingthe hydrophilic, expandable driving member 78 include pectin having amolecular weight ranging from 30,000 to 300,000; polysaccharides such asagar, acacia, karaya, tragacanth, algins and guar; Carbopol® acidiccarboxy polymer and its salt derivatives; polyacrylamides;water-swellable indene maleic anhydride polymers; Good-rite® polyacrylicacid having a molecular weight of 80,000 to 200,000; Polyox®polyethylene oxide polymers having a molecular weight of 100,000 to5,000,000; starch graft copolymers; Aqua-Keep® acrylate polymers withwater absorbability of about 400 times its original weight; diesters ofpolyglucan; a mixture of cross-linked poly(vinyl alcohol) andpoly(N-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecularweight of 4,000 to 100,000; and the like. In a preferred embodiment, theexpandable member 78 is formed from polymers and polymeric compositionsthat are thermoformable.

Representative polymers possessing hydrophilic properties are known inU.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893, 4,220,152, 4,327,725,and 4,350,271, all of which are incorporated herein by reference, and inScott et al, Handbook of Common Polymers, CRC Press, Cleveland, Ohio(1971).

The osmotically effective compound that can be blended homogeneously orheterogeneously with the swellable polymer to form a driving member isselected from the osmotically effective solutes that are soluble influid imbibed into the swellable polymer and exhibit an osmotic pressuregradient across the semipermeable housing 80 against an external fluid.Osmotically effective compounds are known also as osmagents. Osmoticallyeffective osmagents useful for the present purpose include magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol,sucrose, glucose and the like. The osmotic pressure in atmospheres (atm)of the osmagents suitable for the invention will be greater than zeroatm, generally from 8 atm up to 500 atm, or higher.

Representative materials for forming the semipermeable housing include,without limitation, semipermeable homopolymers, semipermeablecopolymers, and the like. In one embodiment, typical materials includecellulose esters, cellulose monoesters, cellulose diesters, cellulosetriesters, cellulose ethers, and cellulose ester-ethers, mixturesthereof, and the like. These cellulose polymers have a degree ofsubstitution (D.S.) on their anhydroglucose unit from greater than zeroup to 3, inclusive. By "degree of substitution" is meant the averagenumber of hydroxyl groups originally present on the anhydroglucose unitthat are replaced by a substituting group or converted into anothergroup. The anhydroglucose unit can be partially or completelysubstituted with groups such as acyl, alkanoyl, aroyl, alkyl, alkenyl,alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate,alkylsulfonate, alkylsulfamate, and like semipermeable polymer forminggroups.

The semipermeable materials typically include a member selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tri-cellulose alkanylates, mono-, di- andtri-alkenylates, mono-, di- and tri-aroylates, and the like. Exemplarypolymers include cellulose acetate having a D.S. of 1.8 to 2.3 and anacetyl content of 32% to 39.9%; cellulose diacetate having a D.S. of 1to 2 and an acetyl content of 21% to 35%; cellulose triacetate having aD.S. of 2 to 3 and an acetyl content of 34% to 44.8%; and the like. Morespecific cellulosic polymers include cellulose propionate having a D.S.of 1.8 and a propionyl content of 38.5%; cellulose acetate propionatehaving an acetyl content of 1.5% to 7% and a propionyl content of 39% to42%; cellulose acetate propionate having an acetyl content of 2.5% to3%, an average propionyl content of 39.2% to 45% and a hydroxyl contentof 2.8% to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, anacetyl content of 13% to 15%, and a butyryl content of 34% to 39%;cellulose acetate butyrate having an acetyl content of 2% to 29.5%, abutyryl content of 17% to 53%, and a hydroxyl content of 0.5% to 4.7%;cellulose triacylates having a D.S. of 2.9 to 3, such as cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrioctanoate, and cellulose tripropionate; cellulose diesters having aD.S. of 2.2 to 2.6, such as cellulose disuccinate, cellulosedipalmitate, cellulose dioctanoate, and cellulose dicarpylate; cellulosepropionate morpholinobutyrate; cellulose acetate butyrate; celluloseacetate phthalate; and the like; mixed cellulose esters, such ascellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, cellulose acetate octanoate, cellulose valeratepalmitate, cellulose acetate heptonate, and the like. Semipermeablepolymers are known in U.S. Pat. No. 4,077,407, incorporated herein byreference, and they can be made procedures described in Encyclopedia ofPolymer Science and Technology, Vol. 3, pages 325-354, IntersciencePublishers, Inc., New York (1964).

Additional semipermeable polymers include cellulose acetaldehyde;dimethyl cellulose acetate; cellulose acetate ethylcarbamate; celluloseacetate methylcarbamate; cellulose dimethylaminoacetate; a cellulosecomposition comprising cellulose acetate andhydroxypropylmethylcellulose; a composition comprising cellulose acetateand cellulose acetate butyrate; a cellulose composition comprisingcellulose acetate butyrate and hydroxypropylmethylcellulose;semipermeable polyamides; semipermeable polyurethanes; semipermeablepolysulfanes; semipermeable sulfonated polystyrenes; crosslinked,selectively semipermeable polymers formed by the coprecipitation of apolyanion and a polycation as disclosed in U.S. Pat. Nos. 3,173,876,3,276,586, 3,541,005, 3,541,006 and 3,546,142, all of which areincorporated herein by reference; selectively semipermeable siliconrubbers; semipermeable polymers as disclosed by Loeb and Sourirajan inU.S. Pat. No. 3,133,132, incorporated herein by reference; semipermeablepolystyrene derivatives; semipermeable (polysodiumstyrenesulfonate);semipermeable poly(vinylbenzyltrimethyl) ammonium chloride;semipermeable polymers exhibiting a fluid permeability of 10⁻¹ to 10⁻⁷(cc.mil/cm² hr-atm) expressed as per atmosphere of hydrostatic orosmotic pressure difference across a semipermeable wall. The polymersare known to the art in U.S. Pat. Nos. 3,845,770, 3,916,899 and4,160,020, all of which are incorporated herein by reference; and in J.R. Scott and W. J. Roff, Handbook of Common Polymers, CRC Press,Cleveland, Ohio (1971).

Other materials that can be used to form the semipermeable housing forimparting flexibility and elongation properties to the wall, for makingthe housing less- to non-brittle and to render tear strength, includephthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate,butyl octyl phthalate, straight chain phthalates of six to elevencarbons, diisononyl phthalate, diisodecyl phthalate, and the like. Theplasticizers include nonphthalates such as citric acid esters,triacetin, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate,triisononyl trimellitate, sucrose acetate isobutyrate, epoxidizedsoybean oil, and the like. The amount of plasticizer in the housing,incorporated therein, is about 0.01% to 20% by weight, or higher.

FIG. 5 illustrates a driving member 88 utilizing an osmoticallyeffective solute. The osmotically effective solute is in solution 90which is retained within a rigid housing 92 comprised of a semipermeablemembrane substantially permeable to the passage of an external fluid andsubstantially impermeable to the passage of the osmotically effectivesolute contained in solution 90. The solution 90 is separated from thedrug units, 94 for example, by means of a flexible membrane 96.

The ability of driving member 88 to displace the drug units, 94 forexample, housed within a dispenser depends upon the osmotic pressuregenerated by the solution 90 of the osmotically effective soluteconfined within housing 92. This solution exhibits an osmotic pressuregradient against fluid in the environment into which the dispenser isplaced, and is preferably a saturated aqueous salt solution. To maintainthe solution saturated and therefore to achieve a constant osmoticpressure throughout operation of the dispenser, the housing containingthe solution also contains excess solute in solid form. Variousosmotically effective solutes can be used. These include magnesiumsulfate, magnesium chloride, sodium chloride, potassium sulfate, sodiumcarbonate, sodium sulfite, sodium sulfate, sodium bicarbonate, potassiumacid phthalate, calcium bicarbonate, potassium acid phosphate,raffinose, tartaric acid, succinic acid, calcium succinate, calciumlactate and magnesium succinate. The excess solid can be in the form ofdispersed particles or preferably in the form of a pellet. The solutioncan initially be a solution of the same or of an osmotically effectivesolute different than the solid excess solute.

FIG. 6 illustrates a driving member 98 which is similar in operation tothat of FIG. 5. An elementary osmotic pump 100, such as that disclosedin U.S. Pat. No. 3,845,770, is held rigidly in place in the impermeablehousing 102, being exposed to the environment at surface 104. Externalfluid is imbibed through the semipermeable wall 106 by the osmoticallyeffective solute 108 contained within the pump 100. As the osmoticpressure within the pump 100 increases, solution (external fluid andosmotic solute) is forced through the orifice 110 into chamber 112,thereby exerting pressure on piston 114 which subsequently moves throughthe housing 102 to dispense the drug units 116 contained therein. Inorder for this driving member to be operable, the wall of the housing102 immediately surrounding the pump 100 must be impermeable to thepassage of fluid so that external fluid does not enter chamber 112.Therefore, use of driving member 98 mandates that the housing be atleast in part of an impermeable composition. In this manner, the housingin contact with the drug units can be semipermeable or impermeable.

FIG. 7 illustrates a driving member 118 which operates by means of agas-generating composition 120. Housing 122 is made of a semipermeablematerial which is substantially impermeable to the passage ofgas-generating composition 120, has a low permeability to the passage ofan internally generated gas and is substantially permeable to thepassage of an external fluid. Membrane 124 is made of a semipermeablematerial which is substantially impermeable to the passage ofgas-generating composition 120 and substantially permeable to thepassage of a generated gas. Its main function is to keep thegas-generating composition 120 apart from the drug units contained inthe dispenser.

In operation, external fluid is imbibed through housing 122 tocontinuously wet and dissolve the gas-generating composition 120,causing it to react and produce a large volume of gas. This gas expandsand passes through membrane 124, filling the area 126. This actioncorrespondingly causes pressure to be exerted on the drug unit 128 whichthereby pushes this and the other units contained therein through thehousing 122.

Gas-generating composition 120 consists essentially of a dry compound oran anhydrous mixture of compounds that, when intimately contacted by anexternal fluid that enters the housing 122, generates a gas that exertsa pressure to drive the dispensing system. The composition 120 comprisesa preferably solid acidic material and a preferably solid basic materialthat dissolve and react in the presence of fluid that enters the housing122. This composition may be in powder, crystalline, granular or layeredform. Alternately, the gas-generating composition 120 may be presenthomogeneously or heterogeneously dispersed in a matrix. The matrix is apolymer permeable to the passage of external fluid and permeable to thepassage of the generated gas. The rate of gas generated in thisembodiment is governed by the rate of fluid passage through the polymercoupled with the rate of fluid passage through the housing 122. Suitablematerials are disclosed in U.S. Pat. No. 4,203,441, incorporated hereinby reference.

Another embodiment of the dispensing configuration of this invention isillustrated in FIG. 8. This embodiment is especially suited for deliveryof units which all contain drug, where it is desired to prevent deliveryfrom units which are still contained within the housing. The dispenserof FIG. 8 is comprised of a rigid housing member 130 which is designedwith an outlet means, exit port 132. A plurality of movable discreteunits 134, 136, 138, 140 and 142 are aligned within the housing 130, andare displaced towards the exit port 132 by means of driving member 144.The drug units are similar in form to those described with reference toFIG. 1 but are all drug-containing units rather then drug-containingalternating with non-drug-containing units.

In FIG. 8, while the units are contained within the housing they areprotected from exposure to the environmental fluid by means of aplurality of plastic or polyethylene partitions 146, 148, 150, 152 and154. When the dispenser is placed in the environment of use, the drivingmember 144 becomes fluid-activated and linearly displaces the units,first dispelling the partition 146 and then unit 134. As unit 134 isdelivering drug, unit 136 is gradually being displaced towards the exit132 and in the meantime is protected from the environment by partition148.

FIGS. 9-13 illustrate examples of housing structures useful for use withthis invention. These structures and suitable materials therefor arefully described in the copending, coassigned patent application ofMagruder et al, U.S. Ser. No. 07/283,359, filed Dec. 13, 1988,incorporated herein by reference. In general terms, the housingembodiments disclosed therein are described as having two walledsections, one substantially impermeable section which defines thedispensing component and one semipermeable section which defines thedriving component. The driving component is typically an expandablematerial such as is described with reference to expandable member 78 inFIG. 4.

FIG. 9 depicts a partial cross-sectional view of delivery system 156,which comprises housing member 158. Housing member 158 comprises adispensing component identified by a first wall section 160 and adriving component identified by a second wall section 162, whichsurround and define internal compartment 164, which contains a pluralityof drug units, 166 for example. Wall section 160 at its end distant fromexit port 168 defines and forms receiving means 170. Receiving means 170is enlarged slightly for receiving second wall section 162. Wall section162 surrounds the internal compartment area 172 that contains drivingcomponent 174, which is suited for expanding and for occupying space incompartment 172 for delivery of a plurality of drug units from deliverysystem 156. The two wall sections, sections 160 and 162, at receivingend 170 are close in size and they form a tight friction fittherebetween. There is clearance or tolerance in size to allow wallsection 162 a sliding movement into the receiving means 170 of wallsection 160. Wall section 160 and wall section 162 can be telescopedcompletely into a closed and continuous waIled position. Optionally,they can be held together by heat fusion, by an adhesive, or the like.

Wall section 160 comprises a composition that is substantiallyimpermeable to the exchange of fluid, drug and other ingredientscontained in the delivery system 156. Wall section 160, in a presentlypreferred manufacture, is substantially impermeable to the ingress of anexternal fluid to serve as a means for substantially protecting drugunits that may contain a drug which is sensitive to fluid from anexterior fluid present in the environment of use. Wall section 160substantially restricts and prevents fluid from passing through wall 160and entering into compartment 164 in the region containing the drugunits. Wall section 162 comprises in at least a part a semipermeablewall composition that is permeable to the passage of fluid for makingfluid available to an expandable driving means 174 inside compartment172. Wall section 162 is permeable to the passage of fluid and it issubstantially impermeable to the passage of other ingredients containedin delivery system 156. Wall sections 160 and 162 optionally comprise aplasticizer that imparts flexibility and workability to the wall.Housing 158, comprising sections 160 and 162, is non-toxic and, in apresently preferred embodiment, it maintains its physical and chemicalintegrity, that is, housing 158 does not erode during the dispensingperiod.

Compartment 164 optionally comprises a layer 176, which is positionedbetween the drug layer 166 and the driving component 174. Layer 176, ina presently preferred embodiment, comprises a composition that issubstantially impermeable to the passage of fluid and it serves torestrict the passage of fluid present in the expandable driving memberinto the compartment 164 housing the drug units. Layer 176 furtheroperates to essentially maintain the integrity of the drug units and thedriving component 174. Layer 176 acts also to insure that the expandingdriving force generated by the driving component is applied directlyagainst the drug units. In operation, as the driving component 174absorbs and imbibes fluid, it expands and pushes against layer 176,causing it to slide inside compartment 160. Layer 176 moves towards exitport 168, pushing the drug units through exit port 168 for maximizingthe delivery of the drug to a biological environment of use, such aslivestock.

FIG. 10 is a partial cross-sectional view of another housing embodimentof delivery system 178 provided by the invention. In FIG. 10, deliverysystem 178 comprises housing member 180, wall 182 and internalcompartment 184 that contains a plurality of drug units 186. In FIG. 10,wall 182 is continuous and it extends the length of delivery system 178.Wall 182 at its end distant from exit port 188 comprises a receiving end190. Receiving end 190 is designed and adapted for receiving insert 192.Insert 192 is cup-like in shape, or tube-like with a single closed end,and it is made of a composition such as a polymeric composition that ispermeable to the passage of an external fluid. Insert 192 comprises adriving component 194 and a layer or partition 196 that separatesdriving component 194 from the other ingredients present in compartment184. Insert 192 in end 190, in a presently preferred embodiment, isreplaceable and one or more than one insert 192 can be used during theoperation of delivery system 178.

FIG. 11 is a partial cross-sectional view of delivery system 198comprising housing member 200 formed by a first wall section 202 thatsurrounds an internal compartment area containing a plurality of drugunits 204, and a second wall section 206 that surrounds an internalcompartment area comprising at least one means for occupying space inthe compartment. First wall section 202 is provided with receiving means208. Wall 202 at receiving means 208 is thinner and it exhibits smallerinternal dimensions for receiving second section 206 at its open end210. Wall section 206 is thinner at its open end 210 and it exhibitssmaller external dimensions for sliding into receiving end 208 in matedrelation for providing an essentially continuous wall. The two sectionscan be joined together by various techniques such as solvent weld,adhesive bond, thermal weld, ultrasonic weld, spin weld, induction weldor by similar welding or bonding operations. First wall section 202 andsecond wall section 206 in the delivery system 198 seen in FIG. 11 aresubstantially uniform in cross-sectional dimensions, thereby providingdelivery system 198 with substantially uniform dimensions along itscentral axis. In a presently preferred embodiment, delivery system 198comprises a multiplicity of driving components 212, 214, and 216 whichmay comprise like or unlike compositions. Delivery system 198 in apresently preferred manufacture comprises layer 218 that separates thedrug units 204 from the driving components.

FIG. 12 is a partial cross-sectional view of delivery system 220, whichcomprises housing member 222, first wall section 224, second wallsection 226, receiving means 228, and a plurality of drug units 230. InFIG. 12, the first wall section 224 functions as a first body portion ofdelivery system 220 and it is designed for slipping over or forreceiving second wall section 226, which serves as a second bodyportion. The second body portion is telescopically capped by theengaging first body portion 224. In FIG. 12, delivery system 220comprises a partition 232 positioned near the drug units 230 containedwithin the space defined by first section 224, and at the fillingentrance of second section 226 comprises a plurality of driving members234, 236 and 238. The members are presently formed as depots or layersof the same or different member-forming compositions selected from thegroup consisting of the expandable materials disclosed herein.

In FIG. 13, a dosage form 240 is seen in cross-section, which dosagedelivery form 240 is similar in structure and in operation to deliveryform 220 illustrated in FIG. 12 and is comprised of a first wall section242 and a second wall section 244. The second wall section 244 of theembodiment has a tapered end 246 rather than a dome-shaped end.

Another embodiment of the dispensing configuration is shown in FIG. 14,where multiple active agent units can be dispersed simultaneously oralmost simultaneously. The dispenser of FIG. 14 is comprised of a rigidhousing member 250 having two outlet means, exit ports 252 and 254, atopposite ends of the housing. A driving member 256 is present in themiddle of housing 250 between exit ports 252 and 254. A plurality ofmovable discrete units 258, 260 and 262 are aligned within housing 250between exit port 252 and driving member 256. A further plurality ofmovable discrete units 264, 266 and 268 are aligned within housing 250between exit port 254 and driving member 256. This configuration ismerely illustrative, and any number of units may be used in thedispenser.

The driving member 256 may be selected from those discussed previouslyherein; that is, it may include a fluid-swellable composition, anosmotically effective solute, or a gas-generating composition, forexample. The driving member 256 when activated will displace units 258,260 and 262 towards exit port 252, while at the same time displacingunits 264, 266 and 268 towards exit port 254.

FIG. 15 illustrates a further embodiment of the housing and thedispenser system of the invention. The system is comprised of asemipermeable rigid housing member 270 surrounded by a rate-controllingmembrane 272 having an outlet means, exit port 274. A driving member 276is present at the end of the housing 270 opposite from the exit port274. A plurality of movable units 278, 280, 282, 284 and 286 are alignedwithin the housing 270 between exit port 274 and driving member 276. Theunits may be closely aligned, as illustrated, or they may be curved, asis shown in FIG. 2. The number of units shown is for illustrativepurposes only, and any number of units may be used. An inert layer 288may or may not be present to separate the driving member 276 from thedrug units, 278 for example. Layer 288 is comparable to layer 176 inFIG. 9.

Semipermeable housing 270 is substantially permeable to external fluidand substantially impermeable to the ingredients contained in drivingmember 276 or in the drug units, 278 for example. The rate-controllingmembrane 272 is selected from those membranes which will selectivelyallow passage of external fluid therethrough to the semipermeablehousing 270 at a particular, predetermined rate. The membrane 272 willbe substantially impermeable to any ingredients contained in drivingmember 276 or in the drug units, 278 for example.

Driving member 276 is typically a swellable material such as isdescribed with reference to expandable member 78 in FIG. 4. When thedispenser is placed in the fluid environment, that portion of housing270 not enclosed by the rate-controlling membrane 272, that is the areaof the housing exposed to the environment at exit port 274, willdissolve, thus providing an open orifice at the exit port for passage ofthe drug units into the environment. The remaining housing 270 enclosedby rate-controlling membrane 272 will ultimately dissolve as well, asthe fluid passes through membrane 272. However, such dissolution isrelatively slower than that at the exit port, due to the presence ofmembrane 272. When the driving member 276 is activated by fluid passingthrough the rate-controlling membrane 272, it will displace the drugunits sequentially towards and out exit port 274.

The amount of drug incorporated in the units of the dispenser of thisinvention varies widely depending on the particular drug, the desiredtherapeutic effect, and the time span for which it takes the drug to bereleased. Since a variety of units in a variety of sizes, shapes andcompositions are intended to provide complete dosage regimes for therapyfor a variety of maladies, there is no critical upper limit on theamount of drug incorporated in the units of the dispenser. The lowerlimit, too, will depend on the activity of the drug and the time span ofits release from the units. Thus, it is not practical to define a rangefor the therapeutically effective amount of drug to be released by theindividual units or by the dispenser as a whole.

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE II

A delivery system manufactured in the shape of a drug dispensercomprising a dispensing component with an exit port and a drivingcomponent is manufactured as follows. First, an expandable drivingmember is prepared by adding 9.5 liters of water and 500 g of polyvinylpyrrolidone to a stainless steel container and mixing the components for20 hours to obtain a smooth binder solution. Next, 34.6 kg of sodiumCarbomer®, a sodium salt of polyacrylic acid polymer, is sized byforcing it through a 0.028 inch mesh screen in a fluid air mill set at780-800 rpm speed. Then, 33 kg of the screened polymer is transferred tothe granulator bowl of a fluid bed granulator, and 6.6 liters of thebinder solution is slowly sprayed onto the polymer in the granulator.The polymer granules are formed in this manner.

Next, 15 kg of sodium chloride is milled in a mill to a number 21 sizemesh screen. Then, 31.32 kg of the polymer granules of sodium Carbomer®is mixed with 13.68 kg of the milled sodium chloride, and the mix isblended for about an hour. Then, 455 g of magnesium stearate is addedand the ingredients are blended for 10 minutes to produce a homogeneousexpandable driving composition. The composition next is pressed intoosmotically active tablets in a tablet press at a pressure of 500 lbs toproduce a round, flat-faced 30 mg tablet.

The driving component is comprised of a semipermeable wall thatsurrounds a compartment for containing the osmotically active tablet.This wall is prepared as follows. First, 3.85 kg of cellulose acetatebutyrate and 1.15 kg of tributyl citrate are dry mixed in a mixer for 5minutes. This produces a polymer plasticizer blend of a 77/23 ratio forthe semipermeable wall. Next, a rubber mill is used to melt-blend theblend, at a roller temperature of 70° C. The blend is transferred to themoving rollers of the mill and mixed for 3 minutes. Then, after all thematerials are added to the mill, the temperature is raised to 90° C,followed by milling for 2 minutes. Next, the temperature is raised to115° C. and followed by two more minutes of milling, after which thetemperature is increased to 133° C. and followed by six minutes ofmilling the blend, after which the temperature is increased to 144° C.and followed by six minutes of milling the blend. After the rollers arecooled to 50° C., the blend is removed from the mill. The milled blendis cut into strips and passed through a grinder mill, and the resultingparticles are fed into an injection molder and molded into thesemipermeable wall surrounding a compartment with an opened end forreceiving an expandable driving member and for mating with thedispensing component of the delivery system.

Next, the dispensing component of the delivery system is prepared byadding 5 kg of polycarbonate to a hopper dryer and drying the polymer at250° F. for 4 hours. The dry polymer is fed into the hopper of aninjection molder, where a single-cavity hot-tip mold is used toinjection-mold an impermeable wall surrounding a compartment with oneopen end for receiving the drug units and for mating with thesemipermeable wall member, and a second open end which forms the exitport.

Next, the delivery system is assembled by first charging the subassembly(driving component) semipermeable walled member with three osmotictablets. Then, microcrystalline wax is melted and the molten wax ispoured on the top of the osmotic tablets to completely fill to theopened walled member. The charged subassembly is allowed to cool to roomtemperature.

Next, the delivery system subassembly (dispensing component) comprisingthe substantially impermeable wall surrounding the compartment is filledwith a plurality of drug units in the form of compressed tablets, havingthe following composition: 90 wt% porcine somatotropin, 2 wt% polyvinylpyrrolidone, 1 wt% magnesium stearate, 3 wt% hydrogenated vegetable oiland 4 wt% histidine HCl. A suitable dosage of porcine somatotropin isabout 112 mg per system. Therefore, the size and number of units will bedesigned accordingly. Then, the two subassemblies at their opened endsare joined by partially inserting the member comprising the osmotictablets and the wax into the member comprising the drug units (layers).Next, 4 drops of moisture-cured cyanoacrylic adhesive are dropped intothe remaining exposed surface, and the two members are fully insertedand twisted to effect a completed delivery system.

EXAMPLE III

A dispenser according to Example II is prepared. The drug unitcomposition is: 93 wt% porcine somatotropin, 2 wt% polyvinylpyrrolidone, 1 wt% magnesium stearate and 4 wt% histidine HCl. Thehydrogenated vegetable oil is eliminated from the unit composition and,instead, about 50 μl of the vegetable oil is injected into thedispensing component. The dispensing component is then filled with thedrug units and the subassemblies are joined as in Example II.

EXAMPLE IV

A dispenser according to Example II is prepared. When the dispensingcomponent is being filled with the drug units, inert wax spacers arepositioned alternating with the drug-containing units and thesubassemblies are joined as in Example II.

EXAMPLE V

A delivery system in the shape of a drug dispenser generally accordingto FIG. 15 was manufactured as follows.

A swellable driving member was prepared as follows. 68.75 Weight percentPolyox® 303 (polyethylene oxide polymer), 5 wt% Carbopol® 934P (acidiccarboxy polymer), 20 wt% sodium chloride, 5 wt%hydroxypropylmethylcellulose and 1 wt% red ferric oxide (for coloring)were first passed through a 40-mesh screen and then mixed in a Hobart®blender. After the mixture was mixed for 15 minutes, ethanol was slowlyadded (0.1 ml/gm). The resulting wet granulation was passed through a20-mesh screen before air drying overnight at room temperature. Thedried granulation was passed through a 20-mesh screen and blended withmagnesium stearate for 5 to 10 minutes. The composition was pressed intoround, flat-faced, osmotically active tablets of 150 mg weight each.

Each drug unit was prepared by mixing together 93.5 wt% gemfibrozil(Lopid®, a lipid regulating agent sold by Parke-Davis), 3.5 wt%hydroxypropylmethylcellulose, 2 wt% Ac-Di-Sol® (croscarmellose sodium)and 1 wt% magnesium stearate. The composition was pressed into drugunits of 160 mg weight each.

An osmotically active tablet was placed in the end of one half of a size"0" hard gelatin capsule, after which three of the gemfibrozil drugunits were added. A fourth drug unit was placed in the end of the otherhalf of the capsule, and the capsule halves were joined together attheir open ends, by inserting one half into the other, and then sealed.

The sealed capsule was then covered with a rate-controlling membrane ofthe composition: 70 wt% cellulose acetate 398-10, 15 wt% polyethyleneglycol 3350 and 15 wt% Klucel® EF (hydroxypropylcellulose). The membranewas scraped away at the end containing the drug units, exposing aportion of the gelatin capsule, to give an exit port of approximately156 mil diameter. The resulting gemfibrozil delivery system had a 65%drug loading.

The delivery system gave a mean drug release rate of between 35 mg/hrand 40 mg/hr between hours 4 and 16.

EXAMPLE VI

A dispenser according to Example V was prepared. The osmotically activetablet for the driving member had a weight of 250 mg and was composed of68.5 wt% Polyox® 303, 10 wt% Carbopol® 934P, 15 wt% sodium chloride, 5wt% hydroxypropylmethylcellulose, 1 wt% red ferric oxide and 0.5 wt%magnesium stearate.

The drug units were composed of 94 wt% gemfibrozil, 3.5 wt%hydroxypropylmethylcellulose, 2 wt% Ac-Di-Sol®, and 0.5 wt% magnesiumstearate and weighed 128 mg each.

One osmotically active tablet and five drug units were placed in a size"00" hard gelatin capsule. The capsule was joined and sealed and coatedwith the rate-controlling membrane according to Example V, and an exitport was made with an orifice diameter of approximately 250 mil. Themean release rate of the drug was 35.8 mg/hr between hours 4 and 16(exit port pointing up).

EXAMPLE VII

A dispenser according to Example V was prepared, except that twogemfibrozil drug units were alternated with two non-drug-containingunits (blanks) in the capsule so that the initial unit to be releasedfrom the exit port was a blank, followed by a drug unit, a blank, and,lastly, a drug unit. This provided a two-pulse delivery system. Therelease rate of the system (with the exit port pointing up) is shown inFIG. 16.

The non-drug-containing units or blanks were composed of 93 wt% ofAvicel® (microcrystalline cellulose), 5 wt% ofhydroxypropylmethylcellulose and 2 wt% of Ac-Di-Sol®.

EXAMPLE VIII

A dispenser according to Example III is prepared, except that 95 wt%rather than 93 wt% of porcine somatotropin, and 2 wt% of copper sulfaterather than 4 wt% histidine HCl are included in the drug unitcomposition.

This invention has been described in detail with particular reference tocertain preferred embodiments thereof, but it will be understood thatvariations and modifications can be effected within the spirit and scopeof the invention.

We claim:
 1. An active agent dispenser for use in a fluid-containingenvironment comprising, in combination:a. a rigid housing open at oneend to provide outlet means therefor, at least a portion of said housingproximate the end of said housing opposite the outlet means permittingpassage of the fluid in said environment to the interior of saidhousing; b. a fluid-activated driving member within said housing influid transmitting relationship with the fluid passing portion of saidhousing proximate the end of said housing opposite said outlet means,said driving member, upon exposure of said dispenser to said fluidenvironment, being the source of motive power for moving the contents ofsaid housing through said outlet; and c. a plurality of solid, discreteactive agent dosage units containing the active agent longitudinallydisposed within said housing between said driving member and said outletmeans, whereby said active agent units will be sequentially displacedfrom said housing into said fluid environment by said driving memberupon exposure of said dispenser to said fluid environment, at least aportion of said active agent units being adapted to maintain theirchemical and physical integrity while within the housing and to dispensea substantial portion of their active agent content into the fluidenvironment after their displacement from said housing into saidenvironment.
 2. The dispenser of claim 1 wherein said plurality ofactive agent units contain the same active agent.
 3. The dispenser ofclaim 2 wherein said active agent units are separated by non-activeagent-containing units.
 4. The dispenser of claim 1 wherein saidplurality of active agent units contain different active agents.
 5. Thedispenser of claim 4 wherein said active agent units are separated bynon-active agent-containing units.
 6. The dispenser of claim 1 whereinsaid driving member comprises a fluid-swellable composition.
 7. Thedispenser of claim 6 wherein the portion of said housing in contact withsaid fluid-swellable composition is permeable to the passage of fluid.8. The dispenser of claim 1 wherein said driving member comprises anosmotically effective solute.
 9. The dispenser of claim 8 wherein theportion of said housing in contact with said solute is permeable to thepassage of fluid.
 10. The dispenser of claim 9 wherein said solute andsaid active agent units are separated by a flexible membrane.
 11. Thedispenser of claim 1 wherein said driving member comprises an elementaryosmotic pump.
 12. The dispenser of claim 11 wherein the portion of saidhousing between said elementary osmotic pump and said outlet means isimpermeable to the passage of fluid in said environment.
 13. Thedispenser of claim 12 wherein said elementary osmotic pump and saidactive agent units are separated by a movable piston.
 14. The dispenserof claim 1 wherein said driving member comprises a gas-generatingcomposition.
 15. The dispenser of claim 14 wherein the partition of saidhousing in contact with said gas-generating composition is permeable tothe passage of fluid.
 16. The dispenser of claim 15 wherein saidgas-generating composition and said active agent units are separated bya semipermeable membrane.
 17. The dispenser of claim 1 which furthercomprises a density element.
 18. The dispenser of claim 1 wherein saidactive agent is selected from the group consisting of pharmacologicallyactive peptides, protein anabolic hormones, growth promoting hormonesrelated to the endocrine system, porcine growth promoting hormone,bovine growth promoting hormone, equine growth promoting hormone, ovinegrowth promoting hormone, human growth promoting hormone, growthpromoting hormones derived by extraction and concentration frompituitary and hypothalamus glands, growth promoting hormones produced byrecombinant DNA methods, polypeptides, growth hormone, somatropin,somatotropin, somatomedin-C, gonadotropic releasing hormone, folliclestimulating hormone, luteinizing hormone, LH-RH, growth hormonereleasing factor, gonadotropin releasing factor, insulin, colchicine,chorionic gonadotropin, oxytocin, vasopressin, adrenocorticotrophichormone, epidermal growth factor, prolactin, somatostatin, cosyntropin,lypressin, thyrotropin releasing hormone, thyroid stimulating hormone,secretin, pancreozymin, enkephalin, glucagon, prochlorperazineedisylate, ferrous sulfate, aminocaproic acid, potassium chloride,mecamylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, benzphetamine hydrochloride, isoproterenol sulfate,methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanecholchloride, metacholine chloride, pilocarpine hydrochloride, atropinesulfate, methscopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,histidine hydrochloride, copper sulfate, diphenidol, meclizinehydrochloride, prochlorperazine maleate, gemfibrozil, thiethylperazinemaleate, anisindione, diphenadione, erythrityl tetranitrate, digoxin,isoflurophate, reserpine, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, flutamide, nilutamide,chlormadinone acetate, phenaglycodol, allopurinol, aluminum, aspirin,methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone,hydrocorticosterone acetate, cortisone acetate, triamcinolone,17-β-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,estradiol, prednisolone, 17-α-hydroxy-progesterone acetate,19-nor-progesterone, norethindrone, progesterone, norethynodrel, andmixtures thereof.
 19. The dispenser of claim 1 wherein said housingcomprises a first walled section and a second walled section, said firstsection being substantially impermeable to the passage of fluid andadapted to receive said active agent units, and said second sectionbeing permeable to the passage of fluid and adapted to receive saidfluid-activated driving member.
 20. The dispenser of claim 19 whereinsaid active agent units are comprised of about 80-95 wt% active agent,about 2-3 wt% binder, about 0.1-5 wt% lubricant and about 1-17.9 wt%excipients.
 21. The dispenser of claim 20 wherein said units furthercomprise about 1-6 wt% stabilizer.
 22. The dispenser of claim 20 whereinsaid active agent is porcine somatotropin.
 23. The dispenser of claim 22wherein said binder is polyvinyl pyrrolidone, said lubricant ismagnesium stearate and said excipient is hydrogenated vegetable oil. 24.The dispenser of claim 23 which further comprises a stablizer admixedwith said somatotropin.
 25. The dispenser of claim 1 wherein the portionof said housing adjacent to said active agent units is impermeable tothe fluid in said fluid environment.
 26. The dispenser of claim 1wherein the portion of said housing adjacent said active agent units ispermeable to the fluid in said fluid environment.
 27. The dispenser ofclaim 1 wherein said housing is formed from a material permeable to thefluid in said fluid environment.
 28. The dispenser of claim 1 whereinsaid active agent is selected from the group consisting of pesticides,herbicides, biocides, algicides, rodenticides, fungicides, antioxidants,plant growth promoters, plant growth inhibitors, preservatives,anti-preservatives, disinfectants, sterilization agents, catalysts,chemical reactants, fermentation agents, foods, food supplements,nutrients, cosmetics, drugs, vitamins, sex sterilizants, fertilityinhibitors, fertility promoters, air purifiers and microorganismattenuators.
 29. The dispenser of claim 1 wherein said active agent isselected from the group consisting of human and animal hypnotics,sedatives, psychic energizers, tranquilizers, anticonvulsants, musclerelaxants, antiparkinson agents, analgesics, anti-inflammatories,anesthetics, muscle contractants, antimicrobials, antimalarials,hormonal agents, contraceptive agents, sympathomimetrics, diuretics,lipid regulating agents, antiandrogenic agents, parisiticides,neoplastics, antineoplastics, hypoglycemics, opthalmics, electrolytesand diagnostic agents.
 30. The dispenser of claim 1 which furthercomprises a rate-controlling membrane surrounding said housing and openat one end to provide outlet means.
 31. The dispenser of claim 30wherein said active agent units are comprised of about 80-95 wt% activeagent, about 2-4 wt% binder, about 0.1-5 wt% lubricant and about 1-17.9wt% excipients.
 32. The dispenser of claim 31 wherein said active agentis gemfibrozil.
 33. The dispenser of claim 32 wherein said binder ishydroxypropylmethylcellulose, said lubricant is magnesium stearate andsaid excipient is croscarmellose sodium.
 34. The dispenser of claim 32wherein said driving member comprises a fluid-swellable composition. 35.The dispenser of claim 32 wherein said active agent units are separatedby non-active agent-containing units.